A decrement in spatial learning ability in normal aging has consistently been correlated with blunted receptor signaling mediated through the muscarinic and metabotropic glutamate receptor-G1q/11 signaling transduction system. The role of G1q/11-mediated signaling in learning and memory is not well established, primarily due to the non-specificity of pharmacological agonists to the receptor subtypes coupled to G1q/11. Transgenic mouse models that knocked out G1q or G111 (or both) have proven to be problematic due to motor deficits or lethality. The proposed model will knock down G1q, the predominate G-protein coupled to the M1 muscarinic and Group I metabotropic glutamate receptors, in the hippocampus using RNA interference (RNAi) via delivery by recombinant adeno-associated virus (rAAV). rAAV will transduce the cell bodies of neurons in the hippocampus, suppressing G1q expression in the intrinsic and projection neurons, while leaving G1q in afferents from other nuclei intact. The results from these experiments are significant in that they will define the role of G1q activation in learning and memory and provide proof that the receptor de-coupling observed in aging may be directly related to memory impairment and not simply a spurious correlation. The clarification of the role that this molecule plays in spatial memory will strengthen its possibility as a potential therapeutic target for age-related memory impairment. Lay description: This project will determine if certain correlational changes observed in cell signaling in the aged, learning impaired animal are directly related to memory decline. PUBLIC HEALTH RELEVANCE: Thirty percent of individuals aged 65 or older will show signs of cognitive decline ranging from mild cognitive impairment to severe dementia. The rat model described in this proposal will provide proof of concept that previously observed signaling alterations in the aged, learning impaired rat are due to mechanistic changes in G-protein function. These rat studies will provide pre-clinical data aimed at the development of potential therapies to counteract normal, age-related memory decline.